US6221398B1 - Process for the preparation of respirable particles - Google Patents

Process for the preparation of respirable particles Download PDF

Info

Publication number
US6221398B1
US6221398B1 US08/669,477 US66947796A US6221398B1 US 6221398 B1 US6221398 B1 US 6221398B1 US 66947796 A US66947796 A US 66947796A US 6221398 B1 US6221398 B1 US 6221398B1
Authority
US
United States
Prior art keywords
solvent
particles
inhalation
compound
inhalation compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US08/669,477
Inventor
Edib Jakupovic
Jan Trofast
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
Astra AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=20397958&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US6221398(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Astra AB filed Critical Astra AB
Assigned to ASTRA AKTIEBOLAG reassignment ASTRA AKTIEBOLAG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TROFAST, JAN, JAKUPOVIC, EDIB
Application granted granted Critical
Publication of US6221398B1 publication Critical patent/US6221398B1/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles

Definitions

  • This invention relates to a process for preparing a pharmaceutical powder for inhalation, which powder comprises crystalline particles of an inhalation compound, in particular particles of mass median diameter 10 ⁇ m or less.
  • Inhalation of dry powders has been recognized as a valuable method for the administration of pharmacological agents and in particular those which are useful in the treatment of diseases of the respiratory tract.
  • the utility of the method has been limited by the difficulty in making appropriate doses available to the lower respiratory tract of the patient. In general only a relatively small proportion of any nominal dose will reach the lower respiratory tract of the inhaling patient; the remainder may remain in the inhaler device or be deposited in the mouth and throat of the patient.
  • European Patent No. 437451 discloses a process for producing finely divided solid crystalline powders, comprising dissolving the solid to be finely divided in a liquid carrier solvent to form an injection solution and adding the injection solution to a volume of anti-solvent, which is a supercritical fluid, liquefied compressed gas or dense vapour, sufficient to precipitate or crystallise the solid.
  • European patent application publication number 0 542 314 A1 discloses a method of forming microparticles of a material, involving bringing a supercritical anti-solvent gas into contact with a solution of said material in a solvent at a controlled rate operable to expand the solution and precipitate the material. Needles and globules are formed.
  • U.S. Pat. No. 5,314,506 again not related to powders for inhalation, describes impinging a jet stream of an organic pharmaceutical compound and a jet stream of an anti-solvent, to precipitate small crystals of the organic pharmaceutical compound. Pressurised blow-cans and elevated temperatures are employed, and the crystals obtained range from flakes of up to 25 microns, to needles, and cubes of less than 3 microns.
  • EP 0169618 discloses a method for the preparation of water-insoluble organic compounds such as may be used in suspensions for intravenous injection, as non-crystalline particles. The method involves preparing a solution of the compound in a water-miscible organic solvent and infusing an aqueous precipitating liquid into the organic solution, in most cases in the presence of surfactant.
  • the process of the present invention aims to provide a powder for inhalation comprising crystalline particles of an inhalation compound of mass median diameter less than 10 ⁇ m, irrespective of the substance concerned.
  • the process does not require the use of supercritical media nor the processes of micronizing and conditioning.
  • a process for producing a pharmaceutical powder for inhalation comprising crystalline particles of an inhalation compound, comprising dissolving an inhalation compound to be provided in crystalline particle form in a solvent; and introducing the solution containing the inhalation compound, in droplet form or as a jet stream into an anti-solvent which is miscible with the solvent and which is under agitation, under non-supercritical conditions.
  • the particles of the inhalation compound of the present invention have a mass median diameter of at least 0.1 ⁇ m, more preferably at least 1 ⁇ m.
  • the particles preferably have a mass median diameter of 10 ⁇ m or less, preferably 7 ⁇ m or less. Most preferably the particles have a mass median diameter of 1-6 ⁇ m.
  • mass median diameter is meant that half of the mass of the inhalation compound is made up of particles having a diameter less than the mass median diameter and half of the mass of the inhalation compound is made up of particles having a diameter greater than the mass median diameter.
  • the powder consists of particles of diameter 10 ⁇ m or less; for example at least 75% or at least 90% of the powder consists of particles of diameter 10 ⁇ m or less.
  • the pharmaceutical powder of the present invention may be administered orally or nasally. Where nasal administration is intended the particles of the inhalation compound may have a mass median diameter outside the above preferred ranges.
  • the pharmaceutical powder may comprise a water-soluble inhalation compound, or a water-insoluble inhalation compound.
  • the solution containing the inhalation compound is introduced into the anti-solvent in droplet form or as a jet-stream, for example through a porous filter or one or more nozzles.
  • the present invention it is possible to control the size of particles obtained by controlling any or all of parameters such as the concentration of the compound in the solvent, the rate of addition of the solution into the anti-solvent and the intensity of the agitation such that particles within a specific desired particle size range may be obtained.
  • a powder formulation having good physicochemical stability and needing no mechanical micronization or conditioning is obtained.
  • Medically useful compounds which may be provided in respirable particle form according to the present invention include ⁇ 2-adrenoteceptor agonists, for example salbutamol, terbutaline, rimiterol, fenoterol, reproterol, adrenaline, pirbuterol, isoprenaline, orciprenaline, bitolterol, salmeterol, formoterol, clenbuterol procaterol, broxaterol, picumeterol, TA-2005 ([8-hydroxy-5-(1-hydroxy-2-((2-(4-methoxyphenyl)-1-methylethyl)amino)ethyl)]-2(1H)quinolone), mabuterol; anticholineigic bronchodilators, for example ipratropium bromide; glucocorticosteroids, for example betamethasone, fluticasone, budesonide, tipredane, dexamethasone, beclomethasone, fluo
  • salbutamol and terbutaline may be used as the sulphate; fenoterol as the hydrobromide; salmeterol as the xinafoate; formoterol as the fumarate dihydrate; clenbuterol as the hydrochloride; fluticasone as the propionate; and broxaterol as the monohydrochloride.
  • the medically useful compound is selected from ⁇ 2-adrenoreceptor agonists and glucocorticosteroids.
  • the medically useful compound is selected from salbutamol, preferably as the sulphate, salmeterol, preferably as the xinafoate, formoterol, preferably as the fumarate dihydrate, budesonide, terbutaline, preferably as the sulphate, fluticasone, preferably as the propionate, rofleponide, preferably as the palmitate, and other pharmaceutically acceptable esters and salts and/or solvates thereof
  • Pharmaceutically acceptable additives e.g., carriers, diluents, and penetration enhancers may also be prepared according to the present invention.
  • the process of the present invention may be used to prepare carbohydrates such as lactose, dextrose, melezitose, maltose, mannitol, trehalose and raffinose, as well as salts of fatty acids, bile salts, phospholipids and alkyl glycosides, which may be useful as penetration enhancers.
  • the pharmaceutically acceptable additive may be prepared stately from the medically useful compound, and the powders may then be mixed together, or a powder containing the medically useful compound and additive may be prepared in certain cases, i.e. when the compound and additive have similar solubilities, by dissolving all of the desired substances together in the solvent according to the present invention.
  • the choice of solvent depends upon the solubility of the compound to be dissolved.
  • a substantially saturated or supersaturated solution is obtained.
  • the anti-solvent should be miscible with the solvent in order that a single-phase solvent mixture is formed and should be such that the dissolved compound is precipitated immediately upon contact therewith.
  • water-soluble substances may be dissolved in water or another solvent more polar than the anti-solvent, or a mixture of such solvents, and precipitated with a less polar solvent (the anti-solvent); and substantially water-insoluble substances may be dissolved in a less polar solvent and precipitated with water or another “more polar” solvent (the anti-solvent).
  • a water-soluble substance which is dissolved for example in water may be precipitated with an anti-solvent such as ethyl acetate, acetone, methylethyl ketone (2-butanone), isopropanol, or mixtures of for example 10-20% methanol, isopropanol or ethanol with 80-90% (w/w) methylethyl ketone or isopropanol, while a less water-soluble substance may be dissolved for example in an organic solvent such as methanol, isopropanol or another alcohol, dimethyl sulphoxide, dimethyl formamide, N'N'-dimethyl acetamide or phenol and precipitated with for example water.
  • an anti-solvent such as ethyl acetate, acetone, methylethyl ketone (2-butanone), isopropanol, or mixtures of for example 10-20% methanol, isopropanol or ethanol with 80-90% (w/w)
  • the solution is added to the anti-solvent at temper as low as possible, but low temperatures are not essential for the process of the present invention.
  • the solution is added to the anti-solvent at temperatures of below 25° C., for example at around 0° C. or from 0 to 5° C.
  • the solution is preferably added to the anti-solvent though a porous filter having pores of 10-160 microns, such as Pyrex Glass Filters of porosity grades 1-4.
  • the rate of addition may be controlled, for example by using a pump, such as a peristaltic pump when working on a laboratory scale.
  • the agitation may be achieved in various ways such as by means of mechanical stirring with propellers, turbines, paddles, anchor impellers or Ystral equipment, or by using ultrasound waves on or beside the filter or nozzles.
  • the precipitated compound may be dried in conventional manner, for example it may be spray-dried, and may be agglomerated and/or spheronized if desired. No conditioning is necessary as the particles obtained are considered to be completely crystalline.
  • the size of the particles obtained according to the present process may be controlled by adjusting the process parameters, as will be evident to a person skilled in the art. For example, decreasing the concentration of compound in the solvent will lead to smaller particles, and adjusting the rate of addition and/or agitation will alter the particle size by altering the size of the droplet from which the compound is precipitated. Any one, several, or all of the process parameters may be adjusted in order to obtain a particular particle size range. The optimal process parameters in each case may be determined by a person skilled in the art using routine experimentation.
  • Various methods may be employed in order to monitor the crystallinity of the respirable particles of the present invention.
  • Such methods include isothermal micro calorimetry, BET gas adsorption, X-ray powder diffraction and differential scanning calorimetry (DSC).
  • DSC differential scanning calorimetry
  • a solution of budesonide (15 g) in methanol (300 ml) was added to water (450 ml) at a temperature of 0° C., through a glass filter, Pyrex porosity grade 3 (pore index 16-40 microns), and with stirring with ultraturrax equipment.
  • a slurry was obtained, containing particles with a mass median diameter (MMD) of 2.2 microns. 90% of the particles had a diameter of below 5.3 ⁇ m.
  • the slurry was spray dried using a commercially available spray-dryer (Büchi 190), to give a budesonide powder consisting of particles of MMD 2.9 microns having no amorphous character, Le., crystalline particles, determined using powder X-ray measurements. 90%/ of the particles had a diameter of below 5.7 ⁇ m.
  • the particles obtained could be agglomerated for use in dry powder inhalers.
  • a solution of budesonide (2.35 g) in methanol (60 ml) was added to water/ice (200 ml) at a rate of 1 ml/min, through a glass filter with a porosity of 40-90 microns, and with stirring with ultraturrax equipment (4.5).
  • the obtained slurry contained budesonide crystalline particles of MMD 2.79 microns. 90% of the particles had a diameter of below 6.0 ⁇ m.
  • a solution of budesonide (1.5 g) in methanol (80 ml) was added to waterrice (300 ml) at a rate of 1 ml/min, through a Pyrex glass filter of porosity grade 2 (40-100 microns), and with stirring with ultraturrax equipment (4.5).
  • the obtained slurry contained budesonide crystalline particles of MMD 2.60 microns. 90% of the particles had a diameter of below 6.0 ⁇ m.
  • Example 3 The procedure of Example 3 was repeated using a Pyrex glass filter of porosity grade 4 (10-16 microns).
  • the obtained slurry contained budesonide crystalline particles of MMD 2.49 microns. 90% of the particles had a diameter of below 6.0 ⁇ m.
  • a solution of budesonide (3 g) in methanol (90 ml) was added to water/ice (300 ml) at a rate of 1 ml/min, through a Pyrex glass filter of porosity grade 1 (100-160 microns), and with stirring with ultraturrax equipment (4.5).
  • the obtained slurry contained budesonide crystalline particles of MMD 4.76 microns. 90% of the particles had a diameter of below 9.6 ⁇ m.
  • a solution of budesonide (1.2 g) in methanol (50 ml) was added via a peristaltic pump and through a glass filter, Pyrex no. 3 (16-40 microns), to water (200 ml) at 0° C. and with stirring with Ystral agitation equipment.
  • the rate of addition was 3 ml/min and the rate of stirring was 1500 r/min.
  • the slurry obtained contained budesonide crystalline particles of MMD 4.2 microns. 90% of the particles had a diameter of below 8.6 ⁇ m.
  • a solution of lactose (2.0 g) in water was added via a peristaltic pump and through a glass filter, Pyrex no. 3, to a 20% solution of ethanol in methylethyl ketone, with stirring with Ystral agitation equipment.
  • the rate of addition was 3 ml/min and the rate of stirring was 1500 r/min.
  • the slurry obtained contained lactose particles of MMD 5.2 microns. 75% of the particles had a diameter of below 10.0 ⁇ m.
  • a solution of salbutamol sulphate (1 g) in water (7 ml) was added via a peristaltic pump and through a glass filter, Pyrex no. 2, to a 20% solution of ethanol in methylethyl ketone at room temperature, with stirring with Ysral agitation equipment.
  • the rate of addition was 3 ml/min and the rate of stirring was 1500 r/min.
  • the slurry obtained contained salbutamol sulphate crystalline particles of MMD 5.2 microns. 75% of the particles had a diameter of below 10.0 ⁇ m.

Abstract

A process for producing a pharmaceutical powder for inhalation comprising crystalline particles of an inhalation compound, comprising dissolving an inhalation compound in a solvent; and introducing the solution containing the inhalation compound in droplet form or as a jet stream into an anti-solvent which is miscible with the solvent and which is under agitation.

Description

This application is a 371 of PCT SE96/00479, filed Apr. 12, 1996.
FIELD OF THE INVENTION
This invention relates to a process for preparing a pharmaceutical powder for inhalation, which powder comprises crystalline particles of an inhalation compound, in particular particles of mass median diameter 10 μm or less.
BACKGROUND OF THE INVENTION
Inhalation of dry powders has been recognized as a valuable method for the administration of pharmacological agents and in particular those which are useful in the treatment of diseases of the respiratory tract. However, the utility of the method has been limited by the difficulty in making appropriate doses available to the lower respiratory tract of the patient. In general only a relatively small proportion of any nominal dose will reach the lower respiratory tract of the inhaling patient; the remainder may remain in the inhaler device or be deposited in the mouth and throat of the patient.
One major factor determining the proportion of inhalable drug which will reach the lower respiratory tract of a patient is the particle size distribution of the particles emerging from the inhaler device. This particle size distribution is in turn dependent both on the construction and function of the inhaler, and the powder fomuation. The present application is concerned with the nature of the powder formulation. This should have a high integrity of the crystal structure, or crystal habit (as may be measured using X-ray crystallography techniques, for example), high purity and stability, and a particle size within the respirable particle range.
In order to achieve a desired crystal structure and particle sum powder formulations of respirable particles are in general obtained by processes including crytallization from solution followed by micronization However, optimum crystal structure formation and optimum purity may not be obtained in this process, and micronization has associated problems. Prolonged comminution rests in a high energy powder and crystal lattice defects which may be manifested for example in lower stability, and/or hygroscopicity. As micronization results in some amorphous character on the surface of the obtained particles, a “conditioning” step is necessary in order to obtain a particle considered to be completely crystalline. International patent applications PCT/SE91/00186 (WO 92/18110) and PCT/SE94/00780 (WO 95/05805) describe methods of conditioning substances in order to obtain crystalline products. It is an object of the present invention to provide a process for the production of crystalline respirable particles which avoids the necessity for post-crystallisation micronization.
European Patent No. 437451 discloses a process for producing finely divided solid crystalline powders, comprising dissolving the solid to be finely divided in a liquid carrier solvent to form an injection solution and adding the injection solution to a volume of anti-solvent, which is a supercritical fluid, liquefied compressed gas or dense vapour, sufficient to precipitate or crystallise the solid.
European patent application, publication number 0 542 314 A1, discloses a method of forming microparticles of a material, involving bringing a supercritical anti-solvent gas into contact with a solution of said material in a solvent at a controlled rate operable to expand the solution and precipitate the material. Needles and globules are formed.
Neither of the above are directed to powders for inhalation per se, and as they use supercritical media the use of compressed gases and heavy, expensive apparatus is necessitated.
U.S. Pat. No. 5,314,506, again not related to powders for inhalation, describes impinging a jet stream of an organic pharmaceutical compound and a jet stream of an anti-solvent, to precipitate small crystals of the organic pharmaceutical compound. Pressurised blow-cans and elevated temperatures are employed, and the crystals obtained range from flakes of up to 25 microns, to needles, and cubes of less than 3 microns.
EP 0169618 discloses a method for the preparation of water-insoluble organic compounds such as may be used in suspensions for intravenous injection, as non-crystalline particles. The method involves preparing a solution of the compound in a water-miscible organic solvent and infusing an aqueous precipitating liquid into the organic solution, in most cases in the presence of surfactant.
The process of the present invention aims to provide a powder for inhalation comprising crystalline particles of an inhalation compound of mass median diameter less than 10 μm, irrespective of the substance concerned. Thus the process does not require the use of supercritical media nor the processes of micronizing and conditioning.
According to the present invention there is provided a process for producing a pharmaceutical powder for inhalation comprising crystalline particles of an inhalation compound, comprising dissolving an inhalation compound to be provided in crystalline particle form in a solvent; and introducing the solution containing the inhalation compound, in droplet form or as a jet stream into an anti-solvent which is miscible with the solvent and which is under agitation, under non-supercritical conditions.
There is also provided according to the present invention a pharmaceutical powder and a crystalline inhalation compound obtainable by the process of the invention.
Preferably the particles of the inhalation compound of the present invention have a mass median diameter of at least 0.1 μm, more preferably at least 1 μm. Where the powder is intended particularly for oral inhalation, preferably the particles have a mass median diameter of 10 μm or less, preferably 7 μm or less. Most preferably the particles have a mass median diameter of 1-6 μm. By “mass median diameter” is meant that half of the mass of the inhalation compound is made up of particles having a diameter less than the mass median diameter and half of the mass of the inhalation compound is made up of particles having a diameter greater than the mass median diameter. Preferably as much as possible of the powder consists of particles of diameter 10 μm or less; for example at least 75% or at least 90% of the powder consists of particles of diameter 10 μm or less.
The pharmaceutical powder of the present invention may be administered orally or nasally. Where nasal administration is intended the particles of the inhalation compound may have a mass median diameter outside the above preferred ranges.
The pharmaceutical powder may comprise a water-soluble inhalation compound, or a water-insoluble inhalation compound.
The solution containing the inhalation compound is introduced into the anti-solvent in droplet form or as a jet-stream, for example through a porous filter or one or more nozzles.
Through the present invention it is possible to control the size of particles obtained by controlling any or all of parameters such as the concentration of the compound in the solvent, the rate of addition of the solution into the anti-solvent and the intensity of the agitation such that particles within a specific desired particle size range may be obtained. A powder formulation having good physicochemical stability and needing no mechanical micronization or conditioning is obtained.
Medically useful compounds which may be provided in respirable particle form according to the present invention include β2-adrenoteceptor agonists, for example salbutamol, terbutaline, rimiterol, fenoterol, reproterol, adrenaline, pirbuterol, isoprenaline, orciprenaline, bitolterol, salmeterol, formoterol, clenbuterol procaterol, broxaterol, picumeterol, TA-2005 ([8-hydroxy-5-(1-hydroxy-2-((2-(4-methoxyphenyl)-1-methylethyl)amino)ethyl)]-2(1H)quinolone), mabuterol; anticholineigic bronchodilators, for example ipratropium bromide; glucocorticosteroids, for example betamethasone, fluticasone, budesonide, tipredane, dexamethasone, beclomethasone, fluocinolone, triamcinolone acetonide, mometasone and rofleponide; peptides and proteins, for example insulin, immunomodulators, anti-allergic drugs for example sodium cromoglycate and nedocromil sodium; expectorants; mucolytics; antihistamines; cyclooxygenase inhibitors; leukotriene synthesis inhibitors; leukotiene antagonists, PLA2 inhibitors, PKC-inhibitors, PAF antagonists and prophylactics of asthma; or pharmacologically acceptable esters and salts and/or solvates thereof. For example salbutamol and terbutaline may be used as the sulphate; fenoterol as the hydrobromide; salmeterol as the xinafoate; formoterol as the fumarate dihydrate; clenbuterol as the hydrochloride; fluticasone as the propionate; and broxaterol as the monohydrochloride.
Preferably the medically useful compound is selected from β2-adrenoreceptor agonists and glucocorticosteroids.
Most preferably the medically useful compound is selected from salbutamol, preferably as the sulphate, salmeterol, preferably as the xinafoate, formoterol, preferably as the fumarate dihydrate, budesonide, terbutaline, preferably as the sulphate, fluticasone, preferably as the propionate, rofleponide, preferably as the palmitate, and other pharmaceutically acceptable esters and salts and/or solvates thereof
Pharmaceutically acceptable additives e.g., carriers, diluents, and penetration enhancers may also be prepared according to the present invention. For example the process of the present invention may be used to prepare carbohydrates such as lactose, dextrose, melezitose, maltose, mannitol, trehalose and raffinose, as well as salts of fatty acids, bile salts, phospholipids and alkyl glycosides, which may be useful as penetration enhancers. The pharmaceutically acceptable additive may be prepared stately from the medically useful compound, and the powders may then be mixed together, or a powder containing the medically useful compound and additive may be prepared in certain cases, i.e. when the compound and additive have similar solubilities, by dissolving all of the desired substances together in the solvent according to the present invention.
In the process of the present invention, the choice of solvent depends upon the solubility of the compound to be dissolved. Preferably, a substantially saturated or supersaturated solution is obtained. The anti-solvent should be miscible with the solvent in order that a single-phase solvent mixture is formed and should be such that the dissolved compound is precipitated immediately upon contact therewith.
The choice of particular solvent and anti-solvent can be made readily by a person skilled in the art considering the solubility characteristics of the compound to be precipitated. In general, water-soluble substances may be dissolved in water or another solvent more polar than the anti-solvent, or a mixture of such solvents, and precipitated with a less polar solvent (the anti-solvent); and substantially water-insoluble substances may be dissolved in a less polar solvent and precipitated with water or another “more polar” solvent (the anti-solvent). For example, a water-soluble substance which is dissolved for example in water may be precipitated with an anti-solvent such as ethyl acetate, acetone, methylethyl ketone (2-butanone), isopropanol, or mixtures of for example 10-20% methanol, isopropanol or ethanol with 80-90% (w/w) methylethyl ketone or isopropanol, while a less water-soluble substance may be dissolved for example in an organic solvent such as methanol, isopropanol or another alcohol, dimethyl sulphoxide, dimethyl formamide, N'N'-dimethyl acetamide or phenol and precipitated with for example water.
To maximize the degree of precipitation it is desirable that the solution is added to the anti-solvent at temper as low as possible, but low temperatures are not essential for the process of the present invention. Preferably, the solution is added to the anti-solvent at temperatures of below 25° C., for example at around 0° C. or from 0 to 5° C.
According to the present invention the solution is preferably added to the anti-solvent though a porous filter having pores of 10-160 microns, such as Pyrex Glass Filters of porosity grades 1-4.
The rate of addition may be controlled, for example by using a pump, such as a peristaltic pump when working on a laboratory scale.
In order that the droplet or fine jet, as well as the precipitated compound, is efficiently removed from the porous filter or nozzle, it is necessary for the anti-solvent to be under agitation. The agitation may be achieved in various ways such as by means of mechanical stirring with propellers, turbines, paddles, anchor impellers or Ystral equipment, or by using ultrasound waves on or beside the filter or nozzles.
The precipitated compound may be dried in conventional manner, for example it may be spray-dried, and may be agglomerated and/or spheronized if desired. No conditioning is necessary as the particles obtained are considered to be completely crystalline.
The size of the particles obtained according to the present process may be controlled by adjusting the process parameters, as will be evident to a person skilled in the art. For example, decreasing the concentration of compound in the solvent will lead to smaller particles, and adjusting the rate of addition and/or agitation will alter the particle size by altering the size of the droplet from which the compound is precipitated. Any one, several, or all of the process parameters may be adjusted in order to obtain a particular particle size range. The optimal process parameters in each case may be determined by a person skilled in the art using routine experimentation.
Various methods may be employed in order to monitor the crystallinity of the respirable particles of the present invention. Such methods, which are all well known to the skilled person in the art, include isothermal micro calorimetry, BET gas adsorption, X-ray powder diffraction and differential scanning calorimetry (DSC). For example during a recrystallization a large amount of heat is evolved and by monitoring the calometrical signal the sample may be checked for any amorphous content.
The following Examples are intended to illustrate, but not limit, the scope of the present invention. The particle sizes given were measured using a Malvern Master Sizer instrument.
EXAMPLE 1
A solution of budesonide (15 g) in methanol (300 ml) was added to water (450 ml) at a temperature of 0° C., through a glass filter, Pyrex porosity grade 3 (pore index 16-40 microns), and with stirring with ultraturrax equipment.
A slurry was obtained, containing particles with a mass median diameter (MMD) of 2.2 microns. 90% of the particles had a diameter of below 5.3 μm. The slurry was spray dried using a commercially available spray-dryer (Büchi 190), to give a budesonide powder consisting of particles of MMD 2.9 microns having no amorphous character, Le., crystalline particles, determined using powder X-ray measurements. 90%/ of the particles had a diameter of below 5.7 μm.
The particles obtained could be agglomerated for use in dry powder inhalers.
EXAMPLE 2
A solution of budesonide (2.35 g) in methanol (60 ml) was added to water/ice (200 ml) at a rate of 1 ml/min, through a glass filter with a porosity of 40-90 microns, and with stirring with ultraturrax equipment (4.5). The obtained slurry contained budesonide crystalline particles of MMD 2.79 microns. 90% of the particles had a diameter of below 6.0 μm.
EXAMPLE 3
A solution of budesonide (1.5 g) in methanol (80 ml) was added to waterrice (300 ml) at a rate of 1 ml/min, through a Pyrex glass filter of porosity grade 2 (40-100 microns), and with stirring with ultraturrax equipment (4.5). The obtained slurry contained budesonide crystalline particles of MMD 2.60 microns. 90% of the particles had a diameter of below 6.0 μm.
EXAMPLE 4
The procedure of Example 3 was repeated using a Pyrex glass filter of porosity grade 4 (10-16 microns). The obtained slurry contained budesonide crystalline particles of MMD 2.49 microns. 90% of the particles had a diameter of below 6.0 μm.
EXAMPLE 5
A solution of budesonide (3 g) in methanol (90 ml) was added to water/ice (300 ml) at a rate of 1 ml/min, through a Pyrex glass filter of porosity grade 1 (100-160 microns), and with stirring with ultraturrax equipment (4.5). The obtained slurry contained budesonide crystalline particles of MMD 4.76 microns. 90% of the particles had a diameter of below 9.6 μm.
EXAMPLE 6
A solution of budesonide (1.2 g) in methanol (50 ml) was added via a peristaltic pump and through a glass filter, Pyrex no. 3 (16-40 microns), to water (200 ml) at 0° C. and with stirring with Ystral agitation equipment. The rate of addition was 3 ml/min and the rate of stirring was 1500 r/min. The slurry obtained contained budesonide crystalline particles of MMD 4.2 microns. 90% of the particles had a diameter of below 8.6 μm.
EXAMPLE 7
A solution of lactose (2.0 g) in water was added via a peristaltic pump and through a glass filter, Pyrex no. 3, to a 20% solution of ethanol in methylethyl ketone, with stirring with Ystral agitation equipment. The rate of addition was 3 ml/min and the rate of stirring was 1500 r/min. The slurry obtained contained lactose particles of MMD 5.2 microns. 75% of the particles had a diameter of below 10.0 μm.
EXAMPLE 8
A solution of salbutamol sulphate (1 g) in water (7 ml) was added via a peristaltic pump and through a glass filter, Pyrex no. 2, to a 20% solution of ethanol in methylethyl ketone at room temperature, with stirring with Ysral agitation equipment. The rate of addition was 3 ml/min and the rate of stirring was 1500 r/min. The slurry obtained contained salbutamol sulphate crystalline particles of MMD 5.2 microns. 75% of the particles had a diameter of below 10.0 μm.

Claims (23)

What is claimed is:
1. A process for producing a pharmaceutical powder for inhalation, the powder comprising crystalline particles of an inhalation compound selected from the group consisting of salbutamol, terbutaline, rimiterol, fenoterol, reproterol, adrenaline, pirbuterol, isoprenaline, orciprenaline, bitolterol, salmeterol, formoterol, clenbuterol, procaterol, broxaterol, picumeterol, 8-hydroxy-5-(l-hydroxy-2-((2-(4-methoxyphenyl)-1-methylethyl)amino)ethyl)-2(1H)-quinoline, mabuterol, betamethasone, fluticasone, budesonide, tipredane, dexamethasone, beclomethasone, fluocinolone, trianicinolone, acetonide, mometasone, rofleponide, and pharmacologically acceptable esters, salts and solvates of these compounds, the particles having a mass median diameter (MMD) of 10 μm or less, the process comprising
dissolving the inhalation compound in a solvent to form a solution; and
introducing the solution containing the inhalation compound, in droplet form or as a jet stream, into an anti-solvent which is miscible with the solvent and which is under agitation, under non-supercritical conditions and at a temperature of less than 25° C., to form the crystalline particles having a MMD of 10 μm or less.
2. A process as claimed in claim 1 wherein the particles of the inhalation compound have a mass median diameter of 7 μm or less.
3. A process as claimed in claim 1 wherein the particles of the inhalation compound have a mass median diameter of at least 0.1 μm.
4. A process as claimed in claim 1 wherein the particles of the inhalation compound have a mass median diameter of at least 1 μm.
5. A process as claimed in claim 1 wherein the particles of the inhalation compound have a mass median diameter of 1-6 μm.
6. A process as claimed in claim 1 wherein at least 75% of the powder consists of particles having a diameter of 10 μm or less.
7. A process as claimed in claim 1 wherein at least 90% of the powder consists of particles having a diameter of 10 μm or less.
8. A process as claimed in claim 1 wherein the solution containing the inhalation compound is introduced into the anti-solvent through a porous filter.
9. A process as claimed in claim 1 wherein the solution containing the inhalation compound is introduced into the anti-solvent through one or more nozzles.
10. A process as claimed in claim 1 wherein the solution containing the inhalation compound is substantially saturated or supersaturated.
11. A process as claimed in claim 1 wherein the inhalation compound is salbutamol sulphate.
12. A process as claimed in claim 1 wherein the inhalation compound is formoterol fumarate dihydrate.
13. A process as claimed in claim 1 wherein the inhalation compound is budesonide.
14. A process as claimed in claim 1 wherein the inhalation compound is terbutaline sulphate.
15. A process as claimed in claim 1 wherein the inhalation compound is rofleponide palmitate.
16. A process as claimed in claim 1 wherein the inhalation compound is salmeterol xinafoate.
17. A process as claimed in claim 1 wherein the anti-solvent is selected from the group consisting of ethyl acetate, acetone, methylethyl ketone, isopropanol, and mixtures of 10-20% of a first solvent selected from the group consisting of methanol, isopropanol and ethanol with 80-90% of a second solvent selected from the group consisting of methylethylketone and isopropanol.
18. A process as claimed in claim 1 wherein the inhalation compound is substantially water-insoluble, the solvent is less polar than the anti-solvent, and the anti-solvent is water or another polar solvent or nature of polar solvents.
19. A process as claimed in claim 18 wherein the solvent is selected from methanol, isopropanol, dimethylsulphoxide, dimethylformamide, N'N'-dimethyl acetamide and phenol.
20. A process as claimed in claim 1 wherein the solution containing the inhalation compound is added to the anti-solvent at a temperature of from 0° C. to 5° C.
21. A process as claimed in claim 1 wherein agitation of the anti-solvent is achieved by means of mechanical sting, propellers, turbines paddles, anchor impellers or Ystral equipment, or by using ultrasound waves on or beside the filter or nozzles.
22. A pharmaceutical powder obtainable by the process of claim 1, consisting essentially of said crystalline particles having a MMD of 10 μm or less.
23. A pharmaceutical powder for inhalation comprising an inhalation compound obtainable by the process of claim 1, said pharmaceutical powder consisting essentially of particles having a MMD of 10 μm or less.
US08/669,477 1995-04-13 1996-04-12 Process for the preparation of respirable particles Expired - Fee Related US6221398B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE9501384A SE9501384D0 (en) 1995-04-13 1995-04-13 Process for the preparation of respirable particles
SE9501384 1995-04-13
PCT/SE1996/000479 WO1996032095A1 (en) 1995-04-13 1996-04-12 Process for the preparation of respirable particles

Publications (1)

Publication Number Publication Date
US6221398B1 true US6221398B1 (en) 2001-04-24

Family

ID=20397958

Family Applications (1)

Application Number Title Priority Date Filing Date
US08/669,477 Expired - Fee Related US6221398B1 (en) 1995-04-13 1996-04-12 Process for the preparation of respirable particles

Country Status (22)

Country Link
US (1) US6221398B1 (en)
EP (1) EP0820276B1 (en)
JP (1) JPH11503448A (en)
CN (1) CN1102383C (en)
AR (1) AR001624A1 (en)
AT (1) ATE230257T1 (en)
AU (1) AU694863B2 (en)
CA (1) CA2217062A1 (en)
DE (1) DE69625589T2 (en)
DK (1) DK0820276T3 (en)
ES (1) ES2188750T3 (en)
IL (1) IL117841A (en)
IN (1) IN185119B (en)
MY (1) MY117344A (en)
NO (1) NO316209B1 (en)
NZ (1) NZ305515A (en)
PT (1) PT820276E (en)
SA (1) SA96160645B1 (en)
SE (1) SE9501384D0 (en)
TW (1) TW492877B (en)
WO (1) WO1996032095A1 (en)
ZA (1) ZA962596B (en)

Cited By (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1281420A2 (en) * 2001-07-30 2003-02-05 Basf Aktiengesellschaft Crystallisation process using ultrasound
US20030031719A1 (en) * 2000-12-22 2003-02-13 Kipp James E. Method for preparing submicron particle suspensions
US20030049323A1 (en) * 2001-08-29 2003-03-13 Hitt James E. Process to precipitate drug particles
US20030075172A1 (en) * 2001-10-19 2003-04-24 Johnson Keith A. Method and apparatus for dispensing inhalator medicament
US20030140920A1 (en) * 2001-10-26 2003-07-31 Dey L.P. Albuterol inhalation soultion, system, kit and method for relieving symptoms of pediatric asthma
US20030191151A1 (en) * 2001-10-26 2003-10-09 Imtiaz Chaudry Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease
US6632842B2 (en) 2001-10-26 2003-10-14 Dey, L.P. Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease
US20030203930A1 (en) * 2001-10-26 2003-10-30 Imtiaz Chaudry Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease
WO2003094892A1 (en) * 2002-05-07 2003-11-20 Focus Inhalation Oy Conversion of amorphous material to a corresponding crystalline material by spray drying and utilization of the crystalline spray dried material in drug formulations
US20040023935A1 (en) * 2002-08-02 2004-02-05 Dey, L.P. Inhalation compositions, methods of use thereof, and process for preparation of same
US20040028747A1 (en) * 2002-08-06 2004-02-12 Tucker Christopher J. Crystalline drug particles prepared using a controlled precipitation process
US20040028746A1 (en) * 2002-08-06 2004-02-12 Sonke Svenson Crystalline drug particles prepared using a controlled precipitation (recrystallization) process
US6702997B2 (en) 2001-10-26 2004-03-09 Dey, L.P. Albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma
US20040076588A1 (en) * 2002-06-28 2004-04-22 Batycky Richard P. Inhalable epinephrine
US20040105821A1 (en) * 2002-09-30 2004-06-03 Howard Bernstein Sustained release pharmaceutical formulation for inhalation
US20040109826A1 (en) * 2002-12-06 2004-06-10 Dey, L.P. Stabilized albuterol compositions and method of preparation thereof
US20040121003A1 (en) * 2002-12-19 2004-06-24 Acusphere, Inc. Methods for making pharmaceutical formulations comprising deagglomerated microparticles
US20040173139A1 (en) * 2003-03-04 2004-09-09 Kozyuk Oleg V. Hydrodynamic cavitation crystallization device and process
US6814953B2 (en) 2001-04-17 2004-11-09 Dey L.P. Bronchodilating compositions and methods
WO2004096405A1 (en) * 2003-04-29 2004-11-11 Akzo Nobel N.V. Antisolvent solidification process
US20040256749A1 (en) * 2000-12-22 2004-12-23 Mahesh Chaubal Process for production of essentially solvent-free small particles
US6835396B2 (en) 2001-09-26 2004-12-28 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion lyophilization
US20040266890A1 (en) * 2003-03-24 2004-12-30 Kipp James E. Methods and apparatuses for the comminution and stabilization of small particles
US20050013868A1 (en) * 2001-09-26 2005-01-20 Sean Brynjelsen Preparation of submicron sized nanoparticles via dispersion lyophilization
US6875449B1 (en) * 1998-03-26 2005-04-05 Glaxo Wellcome, Inc. Crystal structure
US20050196416A1 (en) * 2004-02-05 2005-09-08 Kipp James E. Dispersions prepared by use of self-stabilizing agents
US20050209099A1 (en) * 2002-12-19 2005-09-22 Chickering Donald E Iii Methods and apparatus for making particles using spray dryer and in-line jet mill
US6951656B2 (en) 2000-12-22 2005-10-04 Baxter International Inc. Microprecipitation method for preparing submicron suspensions
US20060009435A1 (en) * 2004-06-23 2006-01-12 Joseph Kaspi Synthesis and powder preparation of fluticasone propionate
WO2006023460A2 (en) 2004-08-16 2006-03-02 Theravance, Inc. COMPOUNDS HAVING β2 ADRENERGIC RECEPTOR AGONIST AND MUSCARINIC RECEPTOR ANTAGONIST ACTIVITY
US20060069139A1 (en) * 2004-05-05 2006-03-30 Renopharm Ltd. Thiazole-based nitric oxide donors capable of releasing two or more nitric oxide molecules and uses thereof
US20060069138A1 (en) * 2004-05-05 2006-03-30 Renopharm Ltd. Thiazole-based nitric oxide donors having alkyl substuent(s) and uses thereof
US20060073199A1 (en) * 2000-12-22 2006-04-06 Mahesh Chaubal Surfactant systems for delivery of organic compounds
WO2006045795A2 (en) * 2004-10-29 2006-05-04 Akzo Nobel N.V. Processes involving the use of antisolvent crystallization
US20060120972A1 (en) * 2004-11-09 2006-06-08 Peter Engels 9-(N-methyl-piperidyliden-4)-thioxanthene for treatment of pulmonary hypertension
US20060188579A1 (en) * 2003-07-07 2006-08-24 Philippe Rogueda Novel process
WO2006096906A1 (en) * 2005-03-18 2006-09-21 Nanomaterials Technology Pte Ltd Inhalable drug
US20060222710A1 (en) * 2001-10-19 2006-10-05 Kipp James E Composition of and method for preparing stable particles in a frozen aqueous matrix
US20060241130A1 (en) * 2003-01-31 2006-10-26 Ehud Keinan Anti-inflammatory compositions and uses thereof
US20060275219A1 (en) * 2003-06-10 2006-12-07 Taisho Pharmaceutical Co., Ltd. Radial spherical crystallization product, process for producing the same, and dry powder preparation containing the crystallization product
US20060280787A1 (en) * 2005-06-14 2006-12-14 Baxter International Inc. Pharmaceutical formulation of the tubulin inhibitor indibulin for oral administration with improved pharmacokinetic properties, and process for the manufacture thereof
US20070021382A1 (en) * 2004-05-05 2007-01-25 Renopharm Ltd. Nitric oxide donors and uses thereof
US20070026083A1 (en) * 2005-07-28 2007-02-01 Doney John A Method to improve characteristics of spray dried powders and granulated materials, and the products thereby produced
US20070099883A1 (en) * 2005-10-07 2007-05-03 Cheryl Lynn Calis Anhydrous mometasone furoate formulation
US20070134341A1 (en) * 2005-11-15 2007-06-14 Kipp James E Compositions of lipoxygenase inhibitors
US20070143739A1 (en) * 2005-12-16 2007-06-21 Taber Bradley M Iii Method and system for development and use of a user-interface for operations, administration, maintenance and provisioning of a telecommunications system
US20070148211A1 (en) * 2005-12-15 2007-06-28 Acusphere, Inc. Processes for making particle-based pharmaceutical formulations for oral administration
US20070178166A1 (en) * 2005-12-15 2007-08-02 Acusphere, Inc. Processes for making particle-based pharmaceutical formulations for pulmonary or nasal administration
US20070231398A1 (en) * 2004-05-05 2007-10-04 Van Lare Cornelis E J Antisolvent Emulsion Solidification Process
US20080085315A1 (en) * 2006-10-10 2008-04-10 John Alfred Doney Amorphous ezetimibe and the production thereof
EP1930323A1 (en) 2004-03-11 2008-06-11 Theravance, Inc. Biphenyl compounds useful in the synthesis of muscarinic receptor antagonists
US20080152717A1 (en) * 2006-12-14 2008-06-26 Isp Investments, Inc. Amorphous valsartan and the production thereof
US20080181961A1 (en) * 2007-01-26 2008-07-31 Isp Investments, Inc. Amorphous oxcarbazepine and the production thereof
US20080181962A1 (en) * 2007-01-26 2008-07-31 Isp Investments, Inc. Formulation process method to produce spray dried products
US20080181960A1 (en) * 2006-12-21 2008-07-31 Isp Investments, Inc. Carotenoids of enhanced bioavailability
US20080233163A1 (en) * 2004-05-05 2008-09-25 Renopharm Ltd. Thiazole-based Nitric Oxide donors having Acyl substuent(s) and uses thereof
US20080293810A1 (en) * 2007-05-22 2008-11-27 Deepak Tiwari Multi-dose concentrate esmolol with benzyl alcohol
US20080293814A1 (en) * 2007-05-22 2008-11-27 Deepak Tiwari Concentrate esmolol
US20080292558A1 (en) * 2007-05-22 2008-11-27 Deepak Tiwari Colored esmolol concentrate
US20090004282A1 (en) * 2005-07-15 2009-01-01 Linda Sze Tu Method of Particle Formation
US20090152176A1 (en) * 2006-12-23 2009-06-18 Baxter International Inc. Magnetic separation of fine particles from compositions
US20100086611A1 (en) * 2000-12-22 2010-04-08 Baxter International Inc. Method for Treating Infectious Organisms Normally Considered to be Resistant to an Antimicrobial Drug
US20100183725A1 (en) * 2005-07-15 2010-07-22 Map Pharmaceuticals, Inc. Multiple active pharmaceutical ingredients combined in discrete inhalation particles and formulations thereof
US20100226913A1 (en) * 2009-02-06 2010-09-09 University Of Southern California Therapeutic Compositions Comprising Monoterpenes
EP2246345A1 (en) 2003-02-14 2010-11-03 Theravance Inc Biphenyl derivatives having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity
US20100291221A1 (en) * 2009-05-15 2010-11-18 Robert Owen Cook Method of administering dose-sparing amounts of formoterol fumarate-budesonide combination particles by inhalation
US20100298602A1 (en) * 2009-05-19 2010-11-25 Massachusetts Institute Of Technology Systems and methods for microfluidic crystallization
US20100294986A1 (en) * 2009-05-19 2010-11-25 Massachusetts Institute Of Technology Supercritical fluid facilitated particle formation in microfluidic systems
WO2011008809A1 (en) 2009-07-15 2011-01-20 Theravance, Inc. Crystalline freebase forms of a biphenyl compound
US20110229437A1 (en) * 2009-09-17 2011-09-22 Mutual Pharmaceutical Company, Inc. Method of Treating Asthma with Antiviral Agents
US8067032B2 (en) 2000-12-22 2011-11-29 Baxter International Inc. Method for preparing submicron particles of antineoplastic agents
US8114912B2 (en) 2003-07-10 2012-02-14 Mylan Pharmaceuticals, Inc. Bronchodilating β-agonist compositions and methods
WO2012027693A2 (en) 2010-08-27 2012-03-01 Neonc Technologies Inc. Pharmaceutical compositions comprising poh derivatives
US8574630B2 (en) 2010-09-22 2013-11-05 Map Pharmaceuticals, Inc. Corticosteroid particles and method of production
US20140141247A1 (en) * 2011-07-08 2014-05-22 Pfizer Limited Process for the preparation of fluticasone propionate form 1
WO2014140647A1 (en) 2013-03-15 2014-09-18 Verona Pharma Plc Drug combination
US9211269B2 (en) 2010-12-17 2015-12-15 Neonc Technologies Inc. Methods and devices for using isoperillyl alcohol
US20160008287A1 (en) * 2014-07-08 2016-01-14 Amphastar Pharmaceuticals Inc. Micronized insulin, micronized insulin analogues, and methods of manufacturing the same
WO2016115147A1 (en) 2015-01-13 2016-07-21 Neonc Technologies Inc. Pharmaceutical compositions comprising poh derivatives
US9522918B2 (en) 2015-02-12 2016-12-20 Neonc Technologies, Inc. Pharmaceutical compositions comprising perillyl alcohol derivatives
WO2018102412A1 (en) 2016-11-30 2018-06-07 Neonc Technologies, Inc. A perillyl alcohol-3 bromopyruvate conjugate and methods of treating cancer
US10322168B2 (en) 2016-01-07 2019-06-18 Amphastar Pharmaceuticals, Inc. High-purity inhalable particles of insulin and insulin analogues, and high-efficiency methods of manufacturing the same
WO2019157195A1 (en) 2018-02-08 2019-08-15 Neonc Technologies, Inc Methods of permeabilizing the blood brain barrier
US10864213B2 (en) 2014-05-12 2020-12-15 Verona Pharma Plc Treatment
EP3769754A1 (en) 2010-03-03 2021-01-27 Neonc Technologies, Inc. Pharmaceutical compositions comprising monoterpenes
US10993916B2 (en) 2011-10-11 2021-05-04 Chiesi Farmaceutici S.P.A. Crystalline microparticles of a beta-agonist coated with a fatty acid

Families Citing this family (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9501384D0 (en) 1995-04-13 1995-04-13 Astra Ab Process for the preparation of respirable particles
SE9701956D0 (en) 1997-05-23 1997-05-23 Astra Ab New composition of matter
JP2002510310A (en) * 1997-06-27 2002-04-02 アストラ・アクチエボラーグ New combination of anti-asthma drugs
SE9704186D0 (en) * 1997-11-14 1997-11-14 Astra Ab New composition of matter
GB2341120B (en) 1998-09-04 2002-04-17 Aea Technology Plc Controlling uniformity of crystalline precipitates
SE9803770D0 (en) * 1998-11-05 1998-11-05 Astra Ab Dry powder pharmaceutical formulation
SE9804001D0 (en) * 1998-11-23 1998-11-23 Astra Ab New process
GB9826284D0 (en) * 1998-12-01 1999-01-20 Rhone Poulence Rorer Limited Process
GB9826286D0 (en) * 1998-12-01 1999-01-20 Rhone Poulence Rorer Limited Process
GB9828721D0 (en) * 1998-12-24 1999-02-17 Glaxo Group Ltd Novel apparatus and process
GB9905512D0 (en) * 1999-03-10 1999-05-05 Smithkline Beecham Plc Process
GB9919693D0 (en) * 1999-08-19 1999-10-20 Rhone Poulenc Rorer Ltd Process
TWI236930B (en) 2000-05-26 2005-08-01 Pfizer Prod Inc Reactive crystallization method to improve particle size
GB0016002D0 (en) * 2000-06-29 2000-08-23 Glaxo Group Ltd Novel process for preparing crystalline particles
GB0016040D0 (en) * 2000-06-29 2000-08-23 Glaxo Group Ltd Novel process for preparing crystalline particles
GB0015981D0 (en) * 2000-06-29 2000-08-23 Glaxo Group Ltd Novel process for preparing crystalline particles
US20030055026A1 (en) 2001-04-17 2003-03-20 Dey L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
EP1409101B1 (en) 2001-05-05 2006-04-12 Accentus plc Formation of small crystals
WO2003070285A1 (en) * 2002-02-19 2003-08-28 Resolution Chemicals Limited Solvent-based sterilisation of pharmaceuticals
DE10214031A1 (en) * 2002-03-27 2004-02-19 Pharmatech Gmbh Process for the production and application of micro- and nanoparticles by micronization
GB0216700D0 (en) 2002-07-18 2002-08-28 Astrazeneca Ab Process
GB0302673D0 (en) 2003-02-06 2003-03-12 Astrazeneca Ab Pharmaceutical formulations
JP5154078B2 (en) * 2003-02-21 2013-02-27 ザ ユニヴァーシティ オブ バース Particle manufacturing process
DE102005011786A1 (en) * 2005-03-11 2006-09-14 Pharmasol Gmbh Process for preparing ultrafine submicron suspensions
WO2006113309A1 (en) 2005-04-15 2006-10-26 Dr. Reddy's Laboratories Ltd. Lacidipine particles
WO2008057048A1 (en) * 2006-11-09 2008-05-15 Nanomaterials Technology Pte Ltd Nano & micro-sized particles of statin compounds and process for forming same
EP2191821A1 (en) * 2008-11-26 2010-06-02 CHIESI FARMACEUTICI S.p.A. Microparticles comprising a salt of 8-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone having improved adhesion properties for dry powder inhalation
UA118087C2 (en) * 2009-10-01 2018-11-26 Адер Фармасьютікалз, Інк. CORTICOSTEROID COMPOSITION, ORALIZED
CA3023725C (en) 2009-10-22 2021-09-14 Vizuri Health Sciences Llc Methods of producing hydrated flavonoids and use thereof in the preparation of topical compositions
CN101849910B (en) * 2010-05-18 2012-02-22 重庆华邦制药股份有限公司 Preparation method of betamethasone dipropionate micro-particle
CN102134236B (en) * 2011-04-15 2013-07-24 北方民族大学 Preparation method of fine clarithromycin powder
DE102012221219B4 (en) * 2012-11-20 2014-05-28 Jesalis Pharma Gmbh Process for increasing the particle size of crystalline drug microparticles
US20210369667A1 (en) 2019-03-29 2021-12-02 Vizuri Health Sciences Consumer Healthcare, Inc. Compositions and methods for the prevention and treatment of radiation dermatitis, eczema, burns, wounds and certain cancers
CN114262316A (en) * 2021-12-24 2022-04-01 嘉应学院 Nano hesperetin, preparation method thereof and double-homogenate cavitation jet system used in preparation method

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0169618A2 (en) 1984-05-21 1986-01-29 STERILIZATION TECHNICAL SERVICES, Inc. Method for making uniformly sized particles from water-insoluble organic compounds
WO1990003782A2 (en) * 1988-10-05 1990-04-19 The Upjohn Company Finely divided solid crystalline powders via precipitation into an anti-solvent
US4997454A (en) * 1984-05-21 1991-03-05 The University Of Rochester Method for making uniformly-sized particles from insoluble compounds
US5254330A (en) * 1990-01-24 1993-10-19 British Technology Group Ltd. Aerosol carriers
US5314506A (en) * 1990-06-15 1994-05-24 Merck & Co., Inc. Crystallization method to improve crystal structure and size
WO1996032095A1 (en) 1995-04-13 1996-10-17 Astra Aktiebolag Process for the preparation of respirable particles
US5709884A (en) * 1993-08-27 1998-01-20 Astra Aktiebolag Process for conditioning substances

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5639441A (en) * 1992-03-06 1997-06-17 Board Of Regents Of University Of Colorado Methods for fine particle formation

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0169618A2 (en) 1984-05-21 1986-01-29 STERILIZATION TECHNICAL SERVICES, Inc. Method for making uniformly sized particles from water-insoluble organic compounds
US4997454A (en) * 1984-05-21 1991-03-05 The University Of Rochester Method for making uniformly-sized particles from insoluble compounds
WO1990003782A2 (en) * 1988-10-05 1990-04-19 The Upjohn Company Finely divided solid crystalline powders via precipitation into an anti-solvent
US5254330A (en) * 1990-01-24 1993-10-19 British Technology Group Ltd. Aerosol carriers
US5314506A (en) * 1990-06-15 1994-05-24 Merck & Co., Inc. Crystallization method to improve crystal structure and size
US5709884A (en) * 1993-08-27 1998-01-20 Astra Aktiebolag Process for conditioning substances
WO1996032095A1 (en) 1995-04-13 1996-10-17 Astra Aktiebolag Process for the preparation of respirable particles

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Herbert A. Lieberman et al., "Disperse Systems", 1988, Marcel Dekker, Inc., vol. I, New York.
Lewis W. Dittert, Ph.D., "An Introduction to Pharmaceutical Techniques and Dosage Forms", 1991, J.B. Lippincott Company, Seventh Edition, Taiwan.

Cited By (141)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6875449B1 (en) * 1998-03-26 2005-04-05 Glaxo Wellcome, Inc. Crystal structure
US8263131B2 (en) 2000-12-22 2012-09-11 Baxter International Inc. Method for treating infectious organisms normally considered to be resistant to an antimicrobial drug
US20030206959A9 (en) * 2000-12-22 2003-11-06 Kipp James E. Method for preparing submicron particle suspensions
US20050170002A1 (en) * 2000-12-22 2005-08-04 Kipp James E. Method for preparing submicron particle suspensions
US20100086611A1 (en) * 2000-12-22 2010-04-08 Baxter International Inc. Method for Treating Infectious Organisms Normally Considered to be Resistant to an Antimicrobial Drug
US20030031719A1 (en) * 2000-12-22 2003-02-13 Kipp James E. Method for preparing submicron particle suspensions
US20040256749A1 (en) * 2000-12-22 2004-12-23 Mahesh Chaubal Process for production of essentially solvent-free small particles
US9700866B2 (en) 2000-12-22 2017-07-11 Baxter International Inc. Surfactant systems for delivery of organic compounds
US20060073199A1 (en) * 2000-12-22 2006-04-06 Mahesh Chaubal Surfactant systems for delivery of organic compounds
US8067032B2 (en) 2000-12-22 2011-11-29 Baxter International Inc. Method for preparing submicron particles of antineoplastic agents
US6951656B2 (en) 2000-12-22 2005-10-04 Baxter International Inc. Microprecipitation method for preparing submicron suspensions
US6814953B2 (en) 2001-04-17 2004-11-09 Dey L.P. Bronchodilating compositions and methods
EP1281420A3 (en) * 2001-07-30 2003-02-26 Basf Aktiengesellschaft Crystallisation process using ultrasound
US20030051659A1 (en) * 2001-07-30 2003-03-20 Matthias Rauls Small particle-adjustment crystallization process
US7128784B2 (en) 2001-07-30 2006-10-31 Basf Aktiengesellschaft Small particle-adjustment crystallization process
EP1281420A2 (en) * 2001-07-30 2003-02-05 Basf Aktiengesellschaft Crystallisation process using ultrasound
WO2003032951A1 (en) * 2001-08-29 2003-04-24 Dow Global Technologies Inc. A process for preparing crystalline drug particles by means of precipitation
US20030049323A1 (en) * 2001-08-29 2003-03-13 Hitt James E. Process to precipitate drug particles
US20050013868A1 (en) * 2001-09-26 2005-01-20 Sean Brynjelsen Preparation of submicron sized nanoparticles via dispersion lyophilization
US6835396B2 (en) 2001-09-26 2004-12-28 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion lyophilization
US8722091B2 (en) 2001-09-26 2014-05-13 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion lyophilization
US20060222710A1 (en) * 2001-10-19 2006-10-05 Kipp James E Composition of and method for preparing stable particles in a frozen aqueous matrix
US7931022B2 (en) 2001-10-19 2011-04-26 Respirks, Inc. Method and apparatus for dispensing inhalator medicament
US20030075172A1 (en) * 2001-10-19 2003-04-24 Johnson Keith A. Method and apparatus for dispensing inhalator medicament
US6632842B2 (en) 2001-10-26 2003-10-14 Dey, L.P. Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease
US6702997B2 (en) 2001-10-26 2004-03-09 Dey, L.P. Albuterol inhalation solution, system, kit and method for relieving symptoms of pediatric asthma
US20030203930A1 (en) * 2001-10-26 2003-10-30 Imtiaz Chaudry Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease
US20030191151A1 (en) * 2001-10-26 2003-10-09 Imtiaz Chaudry Albuterol and ipratropium inhalation solution, system, kit and method for relieving symptoms of chronic obstructive pulmonary disease
US20030140920A1 (en) * 2001-10-26 2003-07-31 Dey L.P. Albuterol inhalation soultion, system, kit and method for relieving symptoms of pediatric asthma
WO2003094892A1 (en) * 2002-05-07 2003-11-20 Focus Inhalation Oy Conversion of amorphous material to a corresponding crystalline material by spray drying and utilization of the crystalline spray dried material in drug formulations
US20040076588A1 (en) * 2002-06-28 2004-04-22 Batycky Richard P. Inhalable epinephrine
US7947742B2 (en) 2002-06-28 2011-05-24 Civitas Therapeutics, Inc. Inhalable epinephrine
US20040023935A1 (en) * 2002-08-02 2004-02-05 Dey, L.P. Inhalation compositions, methods of use thereof, and process for preparation of same
US20040028746A1 (en) * 2002-08-06 2004-02-12 Sonke Svenson Crystalline drug particles prepared using a controlled precipitation (recrystallization) process
US20040028747A1 (en) * 2002-08-06 2004-02-12 Tucker Christopher J. Crystalline drug particles prepared using a controlled precipitation process
US20040105821A1 (en) * 2002-09-30 2004-06-03 Howard Bernstein Sustained release pharmaceutical formulation for inhalation
US20040109826A1 (en) * 2002-12-06 2004-06-10 Dey, L.P. Stabilized albuterol compositions and method of preparation thereof
US20050079138A1 (en) * 2002-12-19 2005-04-14 Chickering Donald E. Methods for making pharmaceutical formulations comprising microparticles with improved dispersibility, suspendability or wettability
US20060093678A1 (en) * 2002-12-19 2006-05-04 Chickering Donald E Iii Methods for making pharmaceutical formulations comprising deagglomerated microparticles
US20050209099A1 (en) * 2002-12-19 2005-09-22 Chickering Donald E Iii Methods and apparatus for making particles using spray dryer and in-line jet mill
US20060093677A1 (en) * 2002-12-19 2006-05-04 Chickering Donald E Iii Methods for making pharmaceutical formulations comprising deagglomerated microparticles
US20040121003A1 (en) * 2002-12-19 2004-06-24 Acusphere, Inc. Methods for making pharmaceutical formulations comprising deagglomerated microparticles
US20060241130A1 (en) * 2003-01-31 2006-10-26 Ehud Keinan Anti-inflammatory compositions and uses thereof
EP2246345A1 (en) 2003-02-14 2010-11-03 Theravance Inc Biphenyl derivatives having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity
EP3012254A1 (en) 2003-02-14 2016-04-27 Theravance Respiratory Company, LLC Biphenyl derivative and its use for treating pulmonary disorders
US7041144B2 (en) 2003-03-04 2006-05-09 Five Star Technologies, Inc. Hydrodynamic cavitation crystallization process
US20060118034A1 (en) * 2003-03-04 2006-06-08 Kozyuk Oleg V Hydrodynamic cavitation crystallization device and process
US20040173139A1 (en) * 2003-03-04 2004-09-09 Kozyuk Oleg V. Hydrodynamic cavitation crystallization device and process
US7511079B2 (en) 2003-03-24 2009-03-31 Baxter International Inc. Methods and apparatuses for the comminution and stabilization of small particles
US20040266890A1 (en) * 2003-03-24 2004-12-30 Kipp James E. Methods and apparatuses for the comminution and stabilization of small particles
WO2004096405A1 (en) * 2003-04-29 2004-11-11 Akzo Nobel N.V. Antisolvent solidification process
US20060182808A1 (en) * 2003-04-29 2006-08-17 Akzo Nobel N.V. Antisolvent solidification process
US20110268806A1 (en) * 2003-04-29 2011-11-03 Organon Usa, Inc. Antisolvent solidification process
US20060275219A1 (en) * 2003-06-10 2006-12-07 Taisho Pharmaceutical Co., Ltd. Radial spherical crystallization product, process for producing the same, and dry powder preparation containing the crystallization product
US20060188579A1 (en) * 2003-07-07 2006-08-24 Philippe Rogueda Novel process
US8114912B2 (en) 2003-07-10 2012-02-14 Mylan Pharmaceuticals, Inc. Bronchodilating β-agonist compositions and methods
US8623922B2 (en) 2003-07-10 2014-01-07 Dey Pharma, L.P. Bronchodilating Beta-agonist compositions and methods
US9730890B2 (en) 2003-07-10 2017-08-15 Mylan Pharmaceuticals, Inc. Bronchodilating beta-agonist compositions and methods
US20050196416A1 (en) * 2004-02-05 2005-09-08 Kipp James E. Dispersions prepared by use of self-stabilizing agents
EP1930323A1 (en) 2004-03-11 2008-06-11 Theravance, Inc. Biphenyl compounds useful in the synthesis of muscarinic receptor antagonists
US20060183913A1 (en) * 2004-05-05 2006-08-17 Renopharm Ltd. Thiazole-based nitric oxide donors having acyl substuent(s) and uses thereof
US7368577B2 (en) 2004-05-05 2008-05-06 Renopharm Ltd. Thiazole-based nitric oxide donors having aryl substituent(s) and uses thereof
US7968575B2 (en) 2004-05-05 2011-06-28 Renopharm Ltd. Nitric oxide donors and uses thereof
US20060183718A1 (en) * 2004-05-05 2006-08-17 Renopharm Ltd. Thiazole-based nitric oxide donors having aryl substituent(s) and uses thereof
US20070231398A1 (en) * 2004-05-05 2007-10-04 Van Lare Cornelis E J Antisolvent Emulsion Solidification Process
US7332513B2 (en) 2004-05-05 2008-02-19 Renopharm Ltd. Thiazole-based nitric oxide donors having acyl substituent(s) and uses thereof
US20080233163A1 (en) * 2004-05-05 2008-09-25 Renopharm Ltd. Thiazole-based Nitric Oxide donors having Acyl substuent(s) and uses thereof
US20070021382A1 (en) * 2004-05-05 2007-01-25 Renopharm Ltd. Nitric oxide donors and uses thereof
US20060069139A1 (en) * 2004-05-05 2006-03-30 Renopharm Ltd. Thiazole-based nitric oxide donors capable of releasing two or more nitric oxide molecules and uses thereof
US20060069138A1 (en) * 2004-05-05 2006-03-30 Renopharm Ltd. Thiazole-based nitric oxide donors having alkyl substuent(s) and uses thereof
US8134010B2 (en) 2004-05-05 2012-03-13 Renopharm Ltd. Thiazole-based nitric oxide donors having aryl substituent(s) and uses thereof
US7498445B2 (en) 2004-05-05 2009-03-03 Renopharm Ltd. Thiazole-based nitric oxide donors capable of releasing two or more nitric oxide molecules and uses thereof
US7579477B2 (en) 2004-05-05 2009-08-25 Renopharm Ltd. Thiazole-based nitric oxide donors having alkyl substituent(s) and uses thereof
US20060009435A1 (en) * 2004-06-23 2006-01-12 Joseph Kaspi Synthesis and powder preparation of fluticasone propionate
WO2006023460A2 (en) 2004-08-16 2006-03-02 Theravance, Inc. COMPOUNDS HAVING β2 ADRENERGIC RECEPTOR AGONIST AND MUSCARINIC RECEPTOR ANTAGONIST ACTIVITY
WO2006045795A2 (en) * 2004-10-29 2006-05-04 Akzo Nobel N.V. Processes involving the use of antisolvent crystallization
WO2006045795A3 (en) * 2004-10-29 2006-11-09 Akzo Nobel Nv Processes involving the use of antisolvent crystallization
US20060120972A1 (en) * 2004-11-09 2006-06-08 Peter Engels 9-(N-methyl-piperidyliden-4)-thioxanthene for treatment of pulmonary hypertension
US20090186088A1 (en) * 2005-03-18 2009-07-23 Nanomaterials Technology Pte Ltd Inhalable drug
WO2006096906A1 (en) * 2005-03-18 2006-09-21 Nanomaterials Technology Pte Ltd Inhalable drug
US20060280787A1 (en) * 2005-06-14 2006-12-14 Baxter International Inc. Pharmaceutical formulation of the tubulin inhibitor indibulin for oral administration with improved pharmacokinetic properties, and process for the manufacture thereof
US8475845B2 (en) 2005-07-15 2013-07-02 Map Pharmaceuticals, Inc. Method of particle formation
US20090004282A1 (en) * 2005-07-15 2009-01-01 Linda Sze Tu Method of Particle Formation
US20100183725A1 (en) * 2005-07-15 2010-07-22 Map Pharmaceuticals, Inc. Multiple active pharmaceutical ingredients combined in discrete inhalation particles and formulations thereof
US20070026083A1 (en) * 2005-07-28 2007-02-01 Doney John A Method to improve characteristics of spray dried powders and granulated materials, and the products thereby produced
US20070026073A1 (en) * 2005-07-28 2007-02-01 Doney John A Amorphous efavirenz and the production thereof
US10532028B2 (en) 2005-07-28 2020-01-14 Isp Investments Llc Method to improve characteristics of spray dried powders and granulated materials, and the products thereby produced
US20070099883A1 (en) * 2005-10-07 2007-05-03 Cheryl Lynn Calis Anhydrous mometasone furoate formulation
US20070134341A1 (en) * 2005-11-15 2007-06-14 Kipp James E Compositions of lipoxygenase inhibitors
US20070178166A1 (en) * 2005-12-15 2007-08-02 Acusphere, Inc. Processes for making particle-based pharmaceutical formulations for pulmonary or nasal administration
US20070148211A1 (en) * 2005-12-15 2007-06-28 Acusphere, Inc. Processes for making particle-based pharmaceutical formulations for oral administration
US20070143739A1 (en) * 2005-12-16 2007-06-21 Taber Bradley M Iii Method and system for development and use of a user-interface for operations, administration, maintenance and provisioning of a telecommunications system
US20080085315A1 (en) * 2006-10-10 2008-04-10 John Alfred Doney Amorphous ezetimibe and the production thereof
US20080152717A1 (en) * 2006-12-14 2008-06-26 Isp Investments, Inc. Amorphous valsartan and the production thereof
US8613946B2 (en) 2006-12-21 2013-12-24 Isp Investment Inc. Carotenoids of enhanced bioavailability
US20080181960A1 (en) * 2006-12-21 2008-07-31 Isp Investments, Inc. Carotenoids of enhanced bioavailability
US20090152176A1 (en) * 2006-12-23 2009-06-18 Baxter International Inc. Magnetic separation of fine particles from compositions
US20080181961A1 (en) * 2007-01-26 2008-07-31 Isp Investments, Inc. Amorphous oxcarbazepine and the production thereof
US20080181962A1 (en) * 2007-01-26 2008-07-31 Isp Investments, Inc. Formulation process method to produce spray dried products
US10189957B2 (en) 2007-01-26 2019-01-29 Isp Investments Llc Formulation process method to produce spray dried products
US8722736B2 (en) 2007-05-22 2014-05-13 Baxter International Inc. Multi-dose concentrate esmolol with benzyl alcohol
US20080293814A1 (en) * 2007-05-22 2008-11-27 Deepak Tiwari Concentrate esmolol
US20080292558A1 (en) * 2007-05-22 2008-11-27 Deepak Tiwari Colored esmolol concentrate
US8426467B2 (en) 2007-05-22 2013-04-23 Baxter International Inc. Colored esmolol concentrate
US20080293810A1 (en) * 2007-05-22 2008-11-27 Deepak Tiwari Multi-dose concentrate esmolol with benzyl alcohol
US20100226913A1 (en) * 2009-02-06 2010-09-09 University Of Southern California Therapeutic Compositions Comprising Monoterpenes
US8236862B2 (en) 2009-02-06 2012-08-07 University Of Southern California Therapeutic compositions comprising monoterpenes
US10342765B2 (en) 2009-02-06 2019-07-09 University Of Southern California Therapeutic compositions comprising monoterpenes
US20100291221A1 (en) * 2009-05-15 2010-11-18 Robert Owen Cook Method of administering dose-sparing amounts of formoterol fumarate-budesonide combination particles by inhalation
US20100298602A1 (en) * 2009-05-19 2010-11-25 Massachusetts Institute Of Technology Systems and methods for microfluidic crystallization
US20100294986A1 (en) * 2009-05-19 2010-11-25 Massachusetts Institute Of Technology Supercritical fluid facilitated particle formation in microfluidic systems
EP2987490A1 (en) 2009-07-15 2016-02-24 Theravance Biopharma R&D IP, LLC Crystalline freebase forms of a biphenyl compound
WO2011008809A1 (en) 2009-07-15 2011-01-20 Theravance, Inc. Crystalline freebase forms of a biphenyl compound
US20110229437A1 (en) * 2009-09-17 2011-09-22 Mutual Pharmaceutical Company, Inc. Method of Treating Asthma with Antiviral Agents
EP3769754A1 (en) 2010-03-03 2021-01-27 Neonc Technologies, Inc. Pharmaceutical compositions comprising monoterpenes
EP3173080A1 (en) 2010-08-27 2017-05-31 Neonc Technologies Inc. Pharmaceutical compositions comprising poh derivatives
EP2883543A1 (en) 2010-08-27 2015-06-17 Neonc Technologies Inc. Pharmaceutical compositions comprising perillyl alcohol carbamates
EP2898883A1 (en) 2010-08-27 2015-07-29 Neonc Technologies Inc. Pharmaceutical compositions comprising perillyl alcohol carbamates
EP3685835A1 (en) 2010-08-27 2020-07-29 Neonc Technologies, Inc. Pharmaceutical compositions comprising poh derivatives
WO2012027693A2 (en) 2010-08-27 2012-03-01 Neonc Technologies Inc. Pharmaceutical compositions comprising poh derivatives
US9499461B2 (en) 2010-08-27 2016-11-22 Neonc Technologies, Inc. Pharmaceutical compositions comprising POH derivatives
US8916545B2 (en) 2010-08-27 2014-12-23 Neonc Technologies Inc. Pharmaceutical compositions comprising POH derivatives
US8574630B2 (en) 2010-09-22 2013-11-05 Map Pharmaceuticals, Inc. Corticosteroid particles and method of production
US9211269B2 (en) 2010-12-17 2015-12-15 Neonc Technologies Inc. Methods and devices for using isoperillyl alcohol
US20140141247A1 (en) * 2011-07-08 2014-05-22 Pfizer Limited Process for the preparation of fluticasone propionate form 1
US10370402B2 (en) * 2011-07-08 2019-08-06 Pfizer Limited Process for the preparation of fluticasone propionate form 1
US10993916B2 (en) 2011-10-11 2021-05-04 Chiesi Farmaceutici S.P.A. Crystalline microparticles of a beta-agonist coated with a fatty acid
WO2014140648A1 (en) 2013-03-15 2014-09-18 Verona Pharma Plc Drug combination
WO2014140647A1 (en) 2013-03-15 2014-09-18 Verona Pharma Plc Drug combination
US11759467B2 (en) 2014-05-12 2023-09-19 Verona Pharma Plc Treatment
US10864213B2 (en) 2014-05-12 2020-12-15 Verona Pharma Plc Treatment
US10258573B2 (en) * 2014-07-08 2019-04-16 Amphastar Pharmaceuticals, Inc. Micronized insulin and micronized insulin analogues prepared under acidic conditions, and methods of manufacturing the same under acidic conditions
US20160008287A1 (en) * 2014-07-08 2016-01-14 Amphastar Pharmaceuticals Inc. Micronized insulin, micronized insulin analogues, and methods of manufacturing the same
WO2016115147A1 (en) 2015-01-13 2016-07-21 Neonc Technologies Inc. Pharmaceutical compositions comprising poh derivatives
US9522918B2 (en) 2015-02-12 2016-12-20 Neonc Technologies, Inc. Pharmaceutical compositions comprising perillyl alcohol derivatives
EP3872069A1 (en) 2015-02-12 2021-09-01 Neonc Technologies, Inc. Pharmaceutical compositions comprising perillyl alcohol derivatives
US10406210B2 (en) 2016-01-07 2019-09-10 Amphastar Pharmaceuticals, Inc. High-purity inhalable particles of insulin and insulin analogues, and high-efficiency methods of manufacturing the same
US10322168B2 (en) 2016-01-07 2019-06-18 Amphastar Pharmaceuticals, Inc. High-purity inhalable particles of insulin and insulin analogues, and high-efficiency methods of manufacturing the same
US11446360B2 (en) 2016-01-07 2022-09-20 Amphastar Pharmaceutcals, Inc. High-purity inhalable particles of insulin and insulin analogues, and high-efficiency methods of manufacturing the same
WO2018102412A1 (en) 2016-11-30 2018-06-07 Neonc Technologies, Inc. A perillyl alcohol-3 bromopyruvate conjugate and methods of treating cancer
WO2019157195A1 (en) 2018-02-08 2019-08-15 Neonc Technologies, Inc Methods of permeabilizing the blood brain barrier

Also Published As

Publication number Publication date
SE9501384D0 (en) 1995-04-13
IL117841A (en) 2004-01-04
TW492877B (en) 2002-07-01
CN1102383C (en) 2003-03-05
MY117344A (en) 2004-06-30
NO974557L (en) 1997-10-02
EP0820276A1 (en) 1998-01-28
IL117841A0 (en) 1996-08-04
IN185119B (en) 2000-11-18
JPH11503448A (en) 1999-03-26
PT820276E (en) 2003-04-30
ES2188750T3 (en) 2003-07-01
DE69625589T2 (en) 2003-09-25
WO1996032095A1 (en) 1996-10-17
NZ305515A (en) 1999-03-29
NO316209B1 (en) 2003-12-29
DK0820276T3 (en) 2003-03-17
NO974557D0 (en) 1997-10-02
AU694863B2 (en) 1998-07-30
ATE230257T1 (en) 2003-01-15
CN1186428A (en) 1998-07-01
EP0820276B1 (en) 2003-01-02
DE69625589D1 (en) 2003-02-06
ZA962596B (en) 1996-10-14
CA2217062A1 (en) 1996-10-17
SA96160645B1 (en) 2005-07-05
AR001624A1 (en) 1997-11-26
AU5352496A (en) 1996-10-30

Similar Documents

Publication Publication Date Title
US6221398B1 (en) Process for the preparation of respirable particles
EP2321022B1 (en) Process for improving crystallinity
KR100514971B1 (en) Composition Comprising Finely Divided, Crystalline Particles of Budesonide
EP1322300B1 (en) Inhalation particles incorporating a combination of two or more active ingredients
JPH0468285B2 (en)
EP0464171A1 (en) Aerosol carriers.
GB2105189A (en) Inhalation drugs
EP1322301B1 (en) Combination particles for the treatment of asthma
BRPI0316908B1 (en) preparation of sterile aqueous suspensions including micronized crystalline inhalation active ingredients
JP2010500356A (en) Method for producing lactose
JP2008533055A (en) Inhalant
JP2003519171A (en) Inhaled particles
WO2005055978A2 (en) A method of engineering particles for use in the delivery of drugs via inhalation
CA2476621A1 (en) Inhalation powder containing the cgrp antagonist bibn4096 and process for the preparation thereof

Legal Events

Date Code Title Description
AS Assignment

Owner name: ASTRA AKTIEBOLAG, SWEDEN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:JAKUPOVIC, EDIB;TROFAST, JAN;REEL/FRAME:008780/0457;SIGNING DATES FROM 19960415 TO 19960417

FPAY Fee payment

Year of fee payment: 4

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20090424